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UBC Theses and Dissertations

Modeling sALS using toxicants and investigating enhancer regulatory elements as novel sALS risk factors Morrice, Jessica Rebecca Marie


The majority of ALS patients have a sporadic form of ALS (sALS), which lack evidence of a dominantly inherited genetic factor. sALS has long been associated with environmental factors such as toxicants, however a clear causal relationship between the environment and sALS has yet to be demonstrated. It is likely that susceptibility genes predispose individuals to develop sALS, and advances in genetics are now identifying sALS risk genes. The majority of single nucleotide polymorphisms (SNPs) are located in non-coding DNA, and the effort to understand the genetic basis of disease is shifting to focus on non-coding regions. Enhancer regulatory elements (eREs) are a type of regulatory element located in non-coding DNA that function to increase gene expression. However, the role of eREs in ALS remains unknown. Here I investigated if toxicants and/or genetic components can be considered as sALS risk factors. The overall hypothesis of my work is that variants in gene enhancer elements are sALS risk factors, which interact with environmental toxicants to drive motor neuron degeneration. I described the effect of lead (Pb) on motor neuron degeneration and further studied the pathogenesis underlying toxicant-induced degeneration. To screen low frequency variants for eREs, I used sALS summary statistics from a large genome wide association study and identified SNPs in 312 distinct eREs. I further prioritized 13 top candidate eRE target genes using RNA-seq data from laser captured motor neurons from sALS patients. Through functional analysis, I demonstrated that knockdown of nucleoporin 50 (nup50), a component of nuclear pore complex, in vivo in a zebrafish model results in motor neuron degeneration, proposing 4 eREs targeting NUP50 as novel sALS risk factors. Further, I investigated the effect of gene-toxicant interactions and demonstrated the synergistic effects on toxicity despite a lacking motor phenotype. These findings describe pathogenic features underlying toxicant-induced motor neuron degeneration, demonstrate a role of eREs as novel sALS risk factors and highlight the complicated nature of modeling gene-toxicant interactions.

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